Magnetic resonance (MR) imaging is widely regarded as a powerful technique for probing, discovering, and diagnosing the presence and progress of a pathological condition or disease. The MR method of imaging is also regarded as the least invasive of the imaging techniques presently available and does not expose the patient or subject to potentially harmful high-energy radiation, such as X-rays, or radioactive isotopes, such as technetium-99m. Technological developments in both instrumentation and computer software continue to improve the availability and quality of the images produced. Researchers discovered quickly, however, that the relative differences between the chemical and magnetic environments of water molecules, whose proton nuclei provide by far the largest source of measurable signal intensity within the body, whether these molecules be located in organs, tissues, tumors, or in the vascular compartment, are often quite small and, consequently, the resulting images are poorly resolved. Fortunately, this inherent limitation can be overcome by the use of proton relaxation agents, also known as contrast agents, which are absorbed selectively by different types of tissues and/or sets of organs, and thus create a temporary condition in which the magnetic environments of neighboring water molecules are measurably dissimilar.
According to their magnetic properties, there are three general types of MR contrast agents: paramagnetic, ferromagnetic, and superparamagnetic. The weak magnetism of paramagnetic substances arises from the individual unpaired electrons while the stronger magnetism of ferromagnetic and superparamagnetic materials results from the coupling of unpaired electrons made possible by their presence in crystalline lattices. Ferromagnetic materials retain their magnetism in the absence of an applied magnetic field while superparamagnetic materials lose their magnetism when the applied magnetic field is removed. With respect to effects on proton relaxation, paramagnetic agents have been termed T.sub.1 type agents because of their ability to enhance spin-lattice or longitudinal relaxation of proton nuclei. Ferromagnetic agents have been termed T.sub.2 type agents because of their specific effects on T.sub.2, sometimes called the spin-spin or transverse relaxation.
There are three major disadvantages to the use of paramagnetic chelates as vascular MR contrast agents. The first is that many low molecular weight, ionic materials which are commonly used as paramagnetic chelates are hypertonic. The use of hypertonic solutions often results in adverse reactions upon injection. The second disadvantage is that paramagnetic chelates have short blood lifetimes whereas a vascular MR contrast agent should remain confined to the vascular compartment for long periods of time. Third, removal of paramagnetic chelates from the vascular compartment can result in release of the paramagnetic ion from the chelate. Paramagnetic ions of iron, manganese, and gadolinium, for example, are toxic in their free ionic form. Vascular MR contrast agents should have a benign metabolic fate after removal from the vascular compartment. These three disadvantages are explained further below.
Paramagnetic materials that have been used as T.sub.1 contrast agents generally include organic free radicals as well as transition metal salts and chelates. These compounds can be quite soluble and, in the case of most transition metal complexes, are highly charged, ionic species. Due to their relatively low relaxivities (their ability to increase the relaxation rates of protons as a function of dose), high concentrations of transition metal chelates are needed to effect useful alterations in the relaxation times of blood. In addition, the ionic nature of many transition metal ion salts and chelates contributes to the high osmotic pressure of the injected diagnostic solutions. The end result is that solutions of paramagnetic materials, whether they are used as MR agents or not, tend to be hyperosmotic relative to blood. The administration of hyperosmotic solutions into the subject is widely believed to be a major cause of ad actions to radiographic and MR contrast media (See, McClennan, B. L. Diagnostic Imaging Supplement 1987, 16-18 (December); "Contrast Media: Biological Effects and Clinical Application," Vol. Ch, 5 I, Parvez, Z., Moncada, R., and Sovak, M. (Eds.), CRC Press, Boca Raton, Florida (1987)).
The usual approach to the development of MR contrast agents confined to the vascular compartment for long periods of time is to increase the molecular weight of paramagnetic chelates by attaching the chelates to high molecular weight polymers. After injection, high molecular weight forms of the chelates cannot be excreted by glomerular filtration, and consequently have longer residence times within the vascular compartment. High molecular weight forms of chelates can be made by covalently attaching chelators to macromolecules such as human serum albumin (Schmiedl et al. Radiology 1987, 162, 205-210)). With this approach to the design of vascular YR contrast agents, the fate of the gadolinium after degradation of the agent presents serious problems. The long term retention of gadolinium not eliminated by glomerular filtration, and the potential for delayed toxicity from that element, pose major obstacles to the administration of high molecular weight gadolinium chelates to humans.
A major disadvantage of present ferromagnetic contrast agents is that such materials are relatively large and, frankly particulate in character. Frankly particulate materials, those generally having overall dimensions between about 0.5-10 microns, are quickly removed from the blood by the phagocytic action of the cells of the reticuloendothelial system, limiting the duration of their effects on the spin-spin and spin-lattice relaxation times of blood. Hence their usefulness as vascular MR contrast agents is limited. All particulate agents suffer a similar limitation.